Lu Le, Wang Jinlong, Lu Hongwei, Zhang Guoyu, Liu Yang, Wang Jiazhong, Zhang Yafei, Shang Hao, Ji Hong, Chen Xi, Duan Yanxia, Li Yiming
Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157, West 5th Road, Xi'an, Shaanxi 710004, China.
West Hospital Ward 1, Shaanxi Provincial People's Hospital, No.256, Youyi Road(west), Xi'an, Shaanxi 710068, China.
Biochem Biophys Res Commun. 2015 Sep 25;465(3):387-93. doi: 10.1016/j.bbrc.2015.08.012. Epub 2015 Aug 6.
Hepatic stellate cells (HSCs) are the primary sources of extracellular matrix (ECM) in normal and fibrotic liver. Peroxisome proliferator-activated receptor gamma (PPARγ) maintains HSCs in a quiescent state, and its downregulation induces HSC activation. MicroRNAs (miRNAs) can induce PPARγ mRNA degradation, but the mechanism by which miRNAs regulate PPARγ in rat HSCs is unclear. This study aimed to investigate some miRNAs which putatively bind to the 3'-untranslated region (3'-UTR) of PPARγ mRNA, and increase expression of ECM genes in rat HSCs. In carbon tetrachloride injection (CCl4) and common bile duct ligation (CBDL) liver fibrosis models, miRNAs miR-130a, miR-130b, miR-301a, miR-27b and miR-340 levels were found to be increased and PPARγ expression decreased. Overexpression of miR-130a and miR-130b enhanced cell proliferation by involving Runx3. MiR-130a and miR-130b decreased PPARγ expression by targeting the 3'-UTR of PPARγ mRNA in rat HSC-T6 cells. Transforming growth factor-β1 (TGF-β1) may mediate miR-130a and miR-130b overexpression, PPARγ downregulation, and ECM genes overexpression in cell culture. These findings suggest that miR-130a and miR-130b are involved in downregulation of PPARγ in liver fibrosis.
肝星状细胞（HSCs）是正常肝脏和纤维化肝脏中细胞外基质（ECM）的主要来源。过氧化物酶体增殖物激活受体γ（PPARγ）可使肝星状细胞维持静止状态，其下调会诱导肝星状细胞激活。微小RNA（miRNAs）可诱导PPARγ mRNA降解，但miRNAs在大鼠肝星状细胞中调节PPARγ的机制尚不清楚。本研究旨在探究一些可能与PPARγ mRNA的3'-非翻译区（3'-UTR）结合并增加大鼠肝星状细胞中ECM基因表达的miRNAs。在四氯化碳注射（CCl4）和胆总管结扎（CBDL）肝纤维化模型中，发现miR-130a、miR-130b、miR-301a、miR-27b和miR-340的水平升高而PPARγ表达降低。miR-130a和miR-130b的过表达通过涉及Runx3增强细胞增殖。在大鼠肝星状细胞系HSC-T6中，miR-130a和miR-130b通过靶向PPARγ mRNA的3'-UTR降低PPARγ表达。在细胞培养中，转化生长因子-β1（TGF-β1）可能介导miR-130a和miR-130b的过表达、PPARγ的下调以及ECM基因的过表达。这些发现表明，miR-130a和miR-130b参与肝纤维化中PPARγ的下调。
